Melanoma subtypes demonstrate distinct PD-L1 expression profiles.

PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

Conjunctival autograft for pterygium.

BACKGROUND: A pterygium is a fleshy, wing-shaped growth from the conjunctiva, crossing over the limbus onto the cornea. Prevalence ranges widely around the world. Evidence suggests that ultraviolet light is a major contributor in the formation of pterygia. Pterygia impair vision, limit eye movements, and can cause eye irritation, foreign body sensation, and dryness. In some susceptible patients, the pterygium can grow over the entire corneal surface, blocking the visual axis.Surgery is the only effective treatment for pterygium, though recurrences are common. With simple excision techniques (that is, excising the pterygium and leaving bare sclera), the risk of recurrence has been reported to be upwards of 80%. Pterygium excision combined with a tissue graft has a lower risk of recurrence. In conjunctival autograft surgery, conjunctival tissue from another part of the person's eye along with limbal tissue is resected in one piece and used to cover the area from which the pterygium was excised. Another type of tissue graft surgery for pterygium is amniotic membrane graft, whereby a piece of donor amniotic membrane is fixed to the remaining limbus and bare sclera area after the pterygium has been excised. OBJECTIVES: The objective of this review was to assess the safety and effectiveness of conjunctival autograft (with or without adjunctive therapy) compared with amniotic membrane graft (with or without adjunctive therapy) for pterygium. We also planned to determine whether use of MMC yielded better surgical results and to assess the direct and indirect comparative costs of these procedures. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 10, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 21 November 2014), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 23 November 2015. SELECTION CRITERIA: We included in this review randomized controlled trials that had compared conjunctival autograft surgery (with or without adjunctive therapy) with amniotic membrane graft surgery (with or without adjunctive therapy) in people with primary or recurrent pterygium. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results and assessed full-text reports from among the potentially eligible trials. Two review authors independently extracted data from the included trials and assessed the trial characteristics and risk of bias. The primary outcome was the risk of recurrence of pterygium at 3 months and 6 months after surgery. We combined results from individual studies in meta-analyses using random-effects models. Risk of recurrence of pterygium was reported using risk ratios to compare conjunctival autograft with amniotic membrane transplant. MAIN RESULTS: We identified 20 studies that had analyzed a total of 1947 eyes of 1866 participants (individual studies ranged from 8 to 346 participants who were randomized). The studies were conducted in eight different countries: one in Brazil, three in China, three in Cuba, one in Egypt, two in Iran, two in Thailand, seven in Turkey, and one in Venezuela. Overall risk of bias was unclear, as many studies did not provide information on randomization methods or masking to prevent performance and detection bias.The risk ratio for recurrence of pterygium using conjunctival autograft versus amniotic membrane transplant was 0.87 (95% confidence interval (CI) 0.43 to 1.77) and 0.53 (95% CI 0.33 to 0.85) at 3 months and 6 months, respectively. These estimates include participants with primary and recurrent pterygia. We performed a subgroup analysis to compare participants with primary pterygia with participants with recurrent pterygia. For participants with primary pterygia, the risk ratio was 0.92 (95% CI 0.37 to 2.30) and 0.58 (95% CI 0.27 to 1.27) at 3 months and 6 months, respectively. We were only able to estimate the recurrence of pterygia at 6 months for participants with recurrent pterygia, and the risk ratio comparing conjunctival autograft with amniotic membrane transplant was 0.45 (95% CI 0.21 to 0.99). One included study was a doctoral thesis and did not use allocation concealment. When this study was excluded in a sensitivity analysis, the risk ratio for pterygium recurrence at 6 months' follow-up was 0.43 (95% CI 0.30 to 0.62) for participants with primary and recurrent pterygium. One of the secondary outcomes, the proportion of participants with clinical improvement, was analyzed in only one study. This study reported clinical outcome as the risk of non-recurrence, which was seen in 93.8% of participants in the conjunctival limbal autograft group and 93.3% in the amniotic membrane transplant group at 3 months after surgery.We did not analyze data on the need for repeat surgery, vision-related quality of life, and direct and indirect costs of surgery due to an insufficient number of studies reporting these outcomes.Thirteen studies reported adverse events associated with conjunctival autograft surgery and amniotic membrane transplant surgery. Adverse events that occurred in more than one study were granuloma and pyogenic granuloma and increased intraocular pressure. None of the included studies reported that participants had developed induced astigmatism. AUTHORS' CONCLUSIONS: In association with pterygium excision, conjunctival autograft is associated with a lower risk of recurrence at six months' after surgery than amniotic membrane transplant. Participants with recurrent pterygia in particular have a lower risk of recurrence when they receive conjunctival autograft surgery compared with amniotic membrane transplant. There are few studies comparing the two techniques with respect to visual acuity outcomes, and we identified no studies that reported on vision-related quality of life or direct or indirect costs. Comparison of these two procedures in such outcome measures bears further investigation. There were an insufficient number of studies that used adjunctive mitomycin C to estimate the effects on pterygium recurrence following conjunctival autograft or amniotic membrane transplant.

Biome representational in silico karyotyping.

Metagenomic characterization of complex biomes remains challenging. Here we describe a modification of digital karyotyping-biome representational in silico karyotyping (BRISK)-as a general technique for analyzing a defined representation of all DNA present in a sample. BRISK utilizes a Type IIB DNA restriction enzyme to create a defined representation of 27-mer DNAs in a sample. Massively parallel sequencing of this representation allows for construction of high-resolution karyotypes and identification of multiple species within a biome. Application to normal human tissue demonstrated linear recovery of tags by chromosome. We apply this technique to the biome of the oral mucosa and find that greater than 25% of recovered DNA is nonhuman. DNA from 41 microbial species could be identified from oral mucosa of two subjects. Of recovered nonhuman sequences, fewer than 30% are currently annotated. We characterized seven prevalent unknown sequences by chromosome walking and find these represent novel microbial sequences including two likely derived from novel phage genomes. Application of BRISK to archival tissue from a nasopharyngeal carcinoma resulted in identification of Epstein-Barr virus infection. These results suggest that BRISK is a powerful technique for the analysis of complex microbiomes and potentially for pathogen discovery.

Corneal biomechanical properties after laser-assisted in situ keratomileusis and photorefractive keratectomy.

BACKGROUND: The purpose of this study was to evaluate the effects of laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) on corneal biomechanical properties. METHODS: We used the ocular response analyzer to measure corneal hysteresis (CH) and corneal resistance factor (CRF) before and after refractive surgery. RESULTS: In all, 230 eyes underwent LASIK and 115 eyes underwent PRK without mitomycin C (MMC). Both procedures decreased CH and CRF from baseline. When MMC was used after PRK in 20 eyes, it resulted in lower corneal biomechanical properties at 3 months when compared to the other procedures, but all three procedures had similar values at 12 months. CONCLUSION: Significant but similar decreases in corneal biomechanical properties after LASIK, PRK without MMC, and PRK with MMC were noted.

Measurement and use of postoperative anterior chamber depth of fellow eye in refractive outcomes.

PURPOSE: To compare refractive outcomes using fellow-eye postoperative anterior chamber depth (ACD) in intraocular lens (IOL) power calculations with outcomes obtained without fellow-eye data and to assess postoperative ACD stability. SETTING: Johns Hopkins University, Baltimore, Maryland, USA. DESIGN: Consecutive case series. METHODS: The main outcome measures were the optimized median absolute error (MedAE) and ACD at postoperative day 1 and postoperative month 1 measured by optical biometry. A program using the Olsen IOL power formula predicted the postoperative ACD and refractive outcomes and calculated theoretical refractive outcomes of inputting fellow-eye ACD at postoperative day 1 and postoperative month 1. Theoretical results were subtracted from the observed manifest refraction and then optimized. Calculations were repeated for the other eye. RESULTS: In 102 paired eyes, the MedAE was 0.32 diopter (D) (interquartile range, 25% to 75%; range 0.12 to 0.54 D) for Olsen (without fellow-eye data), 0.33 D (range 0.20 to 0.57 D) using fellow-eye postoperative day 1 ACD, and 0.28 D (range 0.13 to 0.51 D) using fellow-eye postoperative month 1 ACD, with a significant difference between the latter 2 MedAE values (P < .0005). In eyes with an Olsen absolute error greater than 0.50 D, use of either ACD in the fellow eye resulted in a smaller MedAE (P ≤ .01). The ACD shallowed by a mean of 148 µm ± 13 (SD). CONCLUSIONS: Use of the fellow-eye postoperative month 1 ACD predicted refractive outcomes better than postoperative day 1 ACD. In eyes with a larger Olsen absolute error, use of either postoperative ACD from the fellow eye would have yielded better results. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Traumatic dislocation of implanted collamer phakic lens: a case report and review of the literature.

PURPOSE: Present a case of dislocation of an Implantable Collamer Lens (ICL) that occurs after blunt trauma and review the published literature on this topic. METHODS: Case report and literature review using PubMed. RESULTS: A 44 year-old male presented to the emergency department with sudden onset of blurry vision after blunt trauma to the left eye. Three years prior, he had undergone bilateral ICL placement for high myopia. On examination, the superotemporal haptic was noted to be dislocated into the anterior chamber, but there was no endothelial touch by the dislocated lens. The patient had an associated hyphema that was medically managed, and 2 weeks after the injury, the patient underwent ICL repositioning. A review of the literature was performed and five previous cases of ICL dislocation were identified. Three of these occurred after blunt trauma. One of these cases was associated with endothelial touch and decompensation and eventually required a descement's stripping endothelial keratoplasty (DSAEK). CONCLUSION: Dislocation of ICLs after blunt trauma is a rare but important potential sequela of the procedure and can lead to corneal decompensation if there is lens-endothelial touch. All patients who suffer blunt dislocation of ICL should be followed long-term after repositioning for signs of endothelial loss and dysfunction.

Incidence rate and occurrence of visually significant cataract formation and corneal decompensation after implantation of Verisyse/Artisan phakic intraocular lens.

PURPOSE: To evaluate the incidence rate and indications for explantation of Verisyse phakic intraocular lenses (pIOLs) over a 13.6 year period. SUBJECTS AND METHODS: Case series describing six cases of explantation of Verisyse pIOLs, out of 213 eyes with Verisyse pIOLs, implanted over a 13.6 year period by one surgeon at one institution, with mean follow-up of 5.6 years per eye. RESULTS: Four pIOLs were removed to facilitate extraction of a visually significant cataract, one was removed due to both cataract formation and development of corneal decompensation, and another was removed due to development of localized peripheral corneal decompensation. The incidence rate of pIOL removal was five per 1,000 patient-years with pIOL. Mean time from insertion of pIOL to cataract removal was 9.3 years (range 4.0-12.6 years). Mean time from insertion of pIOL to development of corneal decompensation was 10 years (range 6.9-13 years). There was no increase in the rate of cataract extraction in the pIOL population compared to the general population. CONCLUSION: Cataracts may develop in patients with pIOLs, necessitating removal of the pIOL. Corneal decompensation is a serious complication that appears to be directly related to pIOLs. Corneal decompensation can occur up to 13 years following implantation of pIOLs, and long-term follow-up is important to monitor for this complication.

Dellen-like keratopathy associated with glaucoma drainage devices.

To report the first case of dellen-like keratopathy with superior corneal thinning associated with implantation of glaucoma drainage devices. A 70-year-old male with a history of primary open angle glaucoma and dry eye disease underwent placement of glaucoma drainage devices with antimetabolite application in both eyes. Prior to placement, minimal refractive error was noted on manifest refraction. Several years later, the patient was referred for decreased vision and corneal irregularity. Examination showed pathologic corneal curvature, superior corneal thinning, and epithelial demarcation lines immediately anterior to the glaucoma drainage devices in both eyes. The epithelium remained intact with no evidence of limbal stem cell deficiency. Manifest refraction revealed a large change in both eyes. Topography was used to confirm the presence of irregular corneal curvature anterior to the glaucoma drainage devices. Dellen-like keratopathy with superior thinning is a rare sequela after implantation of a glaucoma drainage device that must be considered in elderly patients who undergo glaucoma surgery. It is likely related to a combination of tear film alteration related to previously large anterior blebs, antimetabolite application, and aqueous humor flow patterns around the drainage devices. Treatment should focus on lubrication.

In vitro pilot analysis of uniformity, circularity, and concentricity of DSAEK donor endothelial grafts prepared by a microkeratome.

PURPOSE: The aim of this study was to analyze Descemet stripping automated endothelial keratoplasty donor endothelial grafts, prepared by using a microkeratome, in terms of uniformity, circularity, and concentricity. METHODS: In this pilot study, 12 human donor corneas were prepared by means of a microkeratome and imaged using the Visante anterior segment optical coherence tomography along 4 meridians. The microkeratome enters and exits the corneal tissue at an angle, creating a donor graft bed with a uniform stromal (US) thickness in between the angled edges. We termed the angled portion the "nonuniform stromal transitional annulus" (STA), the point of entry and exit of the microkeratome the "epithelium-to-epithelium" (E-E) diameter, and the length of the US bed the "US" diameter. The E-E and US diameters were measured to create a model of each donor graft, from which circularity and concentricity were calculated. The STA length and height were measured, and the slope was calculated. RESULTS: The mean E-E diameter was 10.69 ± 0.32 mm (range, 9.46-11.75 mm) and the mean US diameter was 8.96 ± 0.40 mm (range, 7.62-10.28 mm). The microkeratome generated elliptical rather than circular cuts, with a mean eccentricity of 0.34 ± 0.098 (range, 0.22-0.58). Eccentricity values between 0 and 1 represent ellipses, with zero characterizing a circle. The US ellipses and E-E ellipses were not concentric, with a mean deviation of the centers of the shapes of 177.06 ± 92.06 µm (range, 21.95-322.22 µm). The mean STA length was 0.73 ± 0.31 mm (range, 0.25-1.89 mm), the mean height was 0.43 ± 0.08 mm (range, 0.28-0.64 mm), and the mean slope was 34.11 ± 14.00° (range, 8.43-53.67°). CONCLUSIONS: Microkeratome cuts created nonuniform, noncircular nonconcentric donor grafts. Asymmetry and nonuniformity of donor tissue may help explain suboptimal visual outcomes.

Artificial tears potpourri: a literature review.

Numerous brands and types of artificial tears are available on the market for the treatment of dysfunctional tear syndrome. Past literature has focused on comparing the components of these products on patient's clinical improvement. The wide array of products on the market presents challenges to both clinicians and patients when trying to choose between available tear replacement therapies. Different formulations affect patients based on etiology and severity of disease. In order to provide an unbiased comparison between available tear replacement therapies, we conducted a literature review of existing studies and National Institutes of Health clinical trials on commercially available, brand name artificial tears. Outcomes evaluated in each study, as well as the percent of patients showing clinical and symptomatic improvement, were analyzed. Fifty-one studies evaluating different brands of artificial tears, and their efficacy were identified. Out of the 51 studies, 18 were comparison studies testing brand name artificial tears directly against each other. Nearly all formulations of artificial tears provided significant benefit to patients with dysfunctional tear syndrome, but some proved superior to others. From the study data, a recommended treatment flowchart was derived.

Rate of ectasia and incidence of irregular topography in patients with unidentified preoperative risk factors undergoing femtosecond laser-assisted LASIK.

PURPOSE: To report the rate of postoperative ectasia after laser-assisted in situ keratomileusis (LASIK) with femtosecond laser-assisted flap creation, in a population of patients with no identified preoperative risk factors. METHODS: A retrospective case review of 1,992 eyes (1,364 patients) treated between March 2007 and January 2009 was conducted, with a follow up of over 4 years. After identifying cases of ectasia, all the patient charts were examined retrospectively for preoperative findings suggestive of forme fruste keratoconus (FFKC). RESULTS: Five eyes of four patients with post-LASIK ectasia were identified. All eyes passed preoperative screening and received bilateral LASIK. One of the five patients developed ectasia in both eyes. Three patients retrospectively revealed preoperative topography suggestive of FFKC, while one patient had no identifiable preoperative risk factors. Upon review of all the charts, a total 69 eyes, including four of the five eyes with ectasia, were retrospectively found to have topographies suggestive of FFKC. CONCLUSION: We identified four cases of post-LASIK ectasia that had risk factors for FFKC on reexamination of the chart and one case of post-LASIK ectasia with no identifiable preoperative risk factors. The most conservative screening recommendations would not have precluded this patient from LASIK. The rate of purely iatrogenic post-LASIK ectasia at our center was 0.05% (1/1,992), and the total rate of post-LASIK ectasia for our entire study was 0.25% (1/398). The rate of eyes with unrecognized preoperative FFKC that developed post-LASIK ectasia was 5.8% (1/17).

Angle Kappa and its importance in refractive surgery.

Angle kappa is the difference between the pupillary and visual axis. This measurement is of paramount consideration in refractive surgery, as proper centration is required for optimal results. Angle kappa may contribute to MFIOL decentration and its resultant photic phenomena. Adjusting placement of MFIOLs for angle kappa is not supported by the literature but is likely to help reduce glare and haloes. Centering LASIK in angle kappa patients over the corneal light reflex is safe, efficacious, and recommended. Centering in-between the corneal reflex and the entrance pupil is also safe and efficacious. The literature regarding PRK in patients with an angle kappa is sparse but centering on the corneal reflex is assumed to be similar to centering LASIK on the corneal reflex. Thus, centration of MFIOLs, LASIK, and PRK should be focused on the corneal reflex for patients with a large angle kappa. More research is needed to guide surgeons' approach to angle kappa.